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Titel: Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages
VerfasserIn: Hoppstädter, Jessica
Dembek, Anna
Höring, Marcus
Schymik, Hanna S.
Dahlem, Charlotte
Sultan, Afnan
Wirth, Natalie
Al-Fityan, Salma
Diesel, Britta
Gasparoni, Gilles
Walter, Jörn
Helms, Volkhard
Huwer, Hanno
Simon, Martin
Liebisch, Gerhard
Schulz, Marcel H.
Kiemer, Alexandra K.
Sprache: Englisch
Titel: EBioMedicine
Bandnummer: 72
Seiten: 2352-3964
Verlag/Plattform: Elsevier
Erscheinungsjahr: 2021
Freie Schlagwörter: Non-small cell lung cancer
innate immune response
ABCA1
ABCG1
ATR-101
DDC-Sachgruppe: 500 Naturwissenschaften
Dokumenttyp: Journalartikel / Zeitschriftenartikel
Abstract: Background Based on reports on elevated cholesterol levels in cancer cells, strategies to lower cholesterol synthesis have been suggested as an antitumour strategy. However, cholesterol depletion has also been shown to induce tumour-promoting actions in tumour-associated macrophages (TAMs). Methods We performed lipidomic and transcriptomic analyses of human lung cancer material. To assess whether the TAM phenotype is shaped by secreted factors produced by tumour cells, primary human monocyte-derived macrophages were polarized towards a TAM-like phenotype using tumour cell-conditioned medium. Findings Lipidomic analysis of lung adenocarcinoma (n=29) and adjacent non-tumour tissues (n=22) revealed a significant accumulation of free cholesterol and cholesteryl esters within the tumour tissue. In contrast, cholesterol levels were reduced in TAMs isolated from lung adenocarcinoma tissues when compared with alveolar macrophages (AMs) obtained from adjacent non-tumour tissues. Bulk-RNA-Seq revealed that genes involved in cholesterol biosynthesis and metabolism were downregulated in TAMs, while cholesterol efflux transporters were upregulated. In vitro polarized TAM-like macrophages showed an attenuated lipogenic gene expression signature and exhibited lower cholesterol levels compared with non-polarized macrophages. A genome-wide comparison by bulk RNA-Seq confirmed a high similarity of ex vivo TAMs and in vitro TAM-like macrophages. Modulation of intracellular cholesterol levels by either starving, cholesterol depletion, or efflux transporter inhibition indicated that cholesterol distinctly shapes macrophage gene expression. Interpretation Our data show an opposite dysregulation of cholesterol homeostasis in tumour tissue vs. TAMs. Polarization of in vitro differentiated macrophages by tumour cell-conditioned medium recapitulates key features of ex vivo TAMs.
DOI der Erstveröffentlichung: 10.1016/j.ebiom.2021.103578
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-352456
hdl:20.500.11880/32173
http://dx.doi.org/10.22028/D291-35245
ISSN: 2352-3964
Datum des Eintrags: 12-Jan-2022
Bezeichnung des in Beziehung stehenden Objekts: Supplementary materials
In Beziehung stehendes Objekt: https://ars.els-cdn.com/content/image/1-s2.0-S2352396421003716-mmc1.pdf
Fakultät: NT - Naturwissenschaftlich- Technische Fakultät
Fachrichtung: NT - Biowissenschaften
NT - Pharmazie
Professur: NT - Prof. Dr. Volkhard Helms
NT - Prof. Dr. Alexandra K. Kiemer
NT - Prof. Dr. Jörn Walter
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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